Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols

Partially saturated, fluorine-containing rings are ubiquitous across the drug discovery spectrum. This capitalises upon the biological significance of the native structure and the physicochemical advantages conferred by fluorination. Motivated by the significance of aryl tetralins in bioactive small molecules, a reaction cascade has been validated to generate novel gem-difluorinated isosteres from 1,3-diaryl cyclobutanols in a single operation. Under the Brønsted acidity of the catalysis conditions, an acid-catalysed unmasking/fluorination sequence generates a homoallylic fluoride in situ. This species serves as the substrate for an I(I)/I(III) cycle and is processed, via a phenonium ion rearrangement, to an (isolable) 1,3,3-trifluoride. A final C(sp3)-F bond activation event, enabled by HFIP, forges the difluorinated tetralin scaffold. The cascade is highly modular, enabling the intermediates to be intercepted: this provides an expansive platform for the generation of structural diversity.


Reviewer #2 (Remarks to the Author):
This really is a striking paper which explores methodology exposing really quite exotic structural space. It starts from a slightly unusual but synthetically accessible class of cyclobutanol rings and in a single protocol generates the trifluorinated products 2, and generally in very good yield. This transformation is widely exemplified.
The reaction utilises the in-situ generation of fluoroiodinanes, as electrophiles. This is not an intuitive transformation, and that is what makes the contribution most impressive, but it evolves from a body of work in the Gilmour lab using these reagents, and understanding their mechanism. The process involves carbocation rearrangement, nucleophilic fluorinations with concomitant aryl migration. The versatility is fully explored here and to exciting effect. The reagents are cheap and available and the chemistry appears to be robust. Compounds 2 are then further processed to tetralins containing a geminal difluoromethylene group. This is an attractive ring system in medchem, and the approach introduces fluorine which is well known to have subtle effcect on pharmacokinetics. The transformations to tetralones is also widely exemplified, and in one case an analogue of nafenopin is prepared with apparent ease.
The benzylic fluorine in compounds 2c are readily activated for substitution with O, S, N and C nucelophiles, again offering access to a very wide range of products, and these products are all compatible too with a range of Pd cross-coupling reactions, which offers further access to considerable diversification.
There is clear elegance in this work, and it will be attractive to those involved in bioactives discovery.
I only have minor comments. The isomer trans 1c is mentioned in the text, and the minor isomer of 1c is mentioned in Table 1 legend, but it is not clear what is the structure of cis and what is the structure of trans. Is cis 1c the structure shown in the Scheme? That could be clarified.
The word 'Gratifyingly' is used four times in the text, this frequency could be significantly reduced.
The paper is concise and impressive in its ingenuity. I am very happy to recommend publication.

Reviewer #3 (Remarks to the Author):
This manuscript by Gilmour and coworkers describes a multi-step sequence starting from diarylcyclobutanols and furnishing fluorinated aryl-tetralins. This one-pot reaction involves acidcatalyzed SN1 of the alcohol and trapping of the carbocation intermediate with fluoride, difluorination of the alkene with phenonium rearrangement, and C-F activation leading to Friedel-Crafts cyclization. Individually, each step is known, although their combination together is innovative and non-trivial.
-Homoallylic fluorination of cyclopropylcarbinyl and/or bicyclobutonium and/or cyclobutyl cations (Marek et al, J. Am. Chem. Soc. 2020, 142, 5543-5548, which is not cited here.) -Hypervalent iodine-catalyzed fluorination of alkenes, from this paper's and other authors (references 28-36) -C-F activation of benzylic fluorides with HFIP for Friedel-Crafts (Paquin, reference 38) The novel sequence reported here does allow the synthesis of complex difluorinated tetralins. Some discussion about whether this methodology is preferable to deoxofluorination of the corresponding tetralone would be warranted in order to assess how likely it is that the synthetic approach described here is better to access such compounds. The functional group tolerance of the current method is moderate (mostly halogens) but yields are good considering the one-pot sequence of three chemical transformations. A mention of what functional groups are not tolerated in this reaction would be helpful to assess its limitations. Nonetheless, the authors demonstrate its use for the synthesis of a derivative of nafenopin, which showcases the potential use of this method. Of note, the Supporting Information file is nicely organized and presented. The amount and quality of the NMR characterization data is impressive, and the authors are commended for their work. This paper should be publishable in Nature Communications after minor revisions. Of particular importance, a proposed mechanism with detailed intermediate structures (including rearrangement steps) is needed, either as the reaction design scheme or as a final scheme. This reviewer is particularly skeptical about the proposed nature of the cyclobutyl carbocation intermediate and why it would lead to a homoallylic fluoride product. Creary (J. Org. Chem. 2020, 85, 7086-7096.) has shown that when stabilized cyclobutyl electrophiles are ionized, cyclobutyl and bicyclobutonium cations are formed but eventually provide cyclobutane/cyclobutene products, not homoallylic products. On the other hand, Champagne (10.26434/chemrxiv-2022-h9bq3-v2) has shown that in the Marek system cyclopropylcarbinyl cations are formed and can lead to homoallylic products directly or through homoallylic cations. The latter were always higher in energy, even when the homoallylic position is tertiary and benzylic. As such, this reviewer would hypothesize that in the current system, ionization of cyclobutanols 1 eventually leads to a cyclopropylcarbinyl cation (either directly or through a cyclobutyl/bicyclobutonium intermediate), which would explain the formation of the homoallylic fluoride III without requiring the homoallylic cation II. Some discussion about these possibilities is lacking here.
Minor comments: -Compounds are all racemic, could it be indicated as so in the schemes? -That Olah's reagent is Py•HF is not indicated anywhere in the manuscript. Also, how the amine•HF mixtures are made using Et3N•3HF and Py•HF should be discussed somewhere in the text.
-The impact of solvent quantities should probably be discussed as a function of solute concentration rather than solvent volume (0.5 -2mL), to make it more general.

REVIEWER COMMENTS
• Reviewer #1 (Remarks to the Author): The authors report the synthesis and characterization of gem-Difluorinated Tetralins from cyclobutanols using I(I)/I(III) mediated catalyst. The partially fluorinated scaffolds indeed offer scope for the future development and applications of these molecules in the drug industry, keeping in mind that molecules containing organic fluorine are of significance. But what is missing in this paper is whether these molecules have been screened for improved bioefficacy or not. Is the role of organic fluorine established in comparison to the non-fluorinated analogues of these molecules. Even if the authors have not done these measurements or studies in the current work, I encourage them to undertake such studies to unequivocally establish their claim that these indeed are ubiquitous in the drug discovery spectrum.
Author Response: We thank the referee for his/her/their very generous assessment of the work and for supporting publication in Nature Communications. The referee has raised a very important point regarding the product motifs in drug discovery campaigns. Although we feel that a full biological study in beyond the scope of this methodology investigation, we can disclose that we are working with a lead discovery group to incorporate selected motifs into their module library. Regrettably, we are prohibited from disclosing these findings for proprietary reasons at this time. In Scheme 4 we demonstrated that the compound 3s could be processed to a fluorinated analogues of nafenopoin to demonstrate that the fluorinated tetralins reported are compatible with the types of processes typically leveraged in medicinal chemistry.
A careful look at the crystal structures and the checkCIFs reveal that the data/parameter ratio was poor. The accepted ratio is 8-10. Is there any specific reason for this. Is this related to the morphology of the crystals.
Author Response: This is an excellent point. We agree with the referee that the data/parameter ratio should be, in general, higher than 8-10 for a quality structure determination. Unfortunately, for compound 2e and 12 this ratio is slightly below the value of 8 (7.05 for compound 2e and 7.65 for compound 12). The observed ratio can be rationalised by various factors which include crystal size (very small, plate-like crystals with small size dimensions -0.040 mm for 2e; 0.074/0.096 mm for 12), light atom structures (C, H, O, F) with poor diffraction scattering at large theta angles and large disordered parts of these molecules (70% for compound 2e and 68% for compound 12). We have modified the ESI to include a larger discussion of the X-ray crystal structures (vide infra).
Also there exists disorder in the crystal structure. It will be of relevance if the authors mention the ratio of the two independent conformations in the ESI wherein details on data collection are mentioned.
Author Response: We thank the referee for this helpful suggestion. The corresponding ratio of the twoindependent conformations for the both disordered structures (compounds 2e and 12) have been added to the supporting information and additional information has been added to the manuscript figure legends. For compound 2e this ratio was found to be 80:20 and for compound 12 84:16, respectively. The XP pictures of the two conformers for compound 2e and 12 have also been added to the SI. Fig 2 and remaining places, the ORTEP view depicting the thermal ellipsoids is required as that represents a more realistic view of the atoms in molecules in crystals. Hence the ellipsoidal view from Mercury/any related software must be made and presented.

Also in
Author Response: For all three compounds, the corresponding ORTEP views depicting the thermal ellipsoids with a probability of 50% have been added to the manuscript and ESI. We thank the referee for this helpful suggestion.
Overall, I congratulate the authors on this excellent piece of work in synthesis and characterization of organofluorine compounds. Also, the authors can look at the polymorphic events associated with these compounds and explore the role of weak C-H...F interactions in the crystal packing of these molecules. Keeping in mind the fact that the above-mentioned corrections will be incorporated, I support publication of this manuscript in Nature Communications.

Author Response:
The referee is quite right that an array of interactions can be observed in the packing diagrams. We have added depictions of the three compounds to the supporting information which show weak C-H … F, F … F, C-H … pi or O-H … O interactions. Again, we wish to thank the referee for the detailed and insightful report. Aside from the ongoing biological work, which we feel is beyond the scope of this methodology study and will be disclosed in due course, we hope that the comments and suggestions from referee 1 have been fully addressed.

• Reviewer #2 (Remarks to the Author):
This really is a striking paper which explores methodology exposing really quite exotic structural space. It starts from a slightly unusual but synthetically accessible class of cyclobutanol rings and in a single protocol generates the trifluorinated products 2, and generally in very good yield. This transformation is widely exemplified. The reaction utilises the in-situ generation of fluoroiodinanes, as electrophiles. This is not an intuitive transformation, and that is what makes the contribution most impressive, but it evolves from a body of work in the Gilmour lab using these reagents, and understanding their mechanism. The process involves carbocation rearrangement, nucleophilic fluorinations with concomitant aryl migration. The versatility is fully explored here and to exciting effect. The reagents are cheap and available and the chemistry appears to be robust. Compounds 2 are then further processed to tetralins containing a geminal difluoromethylene group. This is an attractive ring system in medchem, and the approach introduces fluorine which is well known to have subtle effect on pharmacokinetics. The transformations to tetralones is also widely exemplified, and in one case an analogue of nafenopin is prepared with apparent ease.
The benzylic fluorine in compounds 2c are readily activated for substitution with O, S, N and C nucleophiles, again offering access to a very wide range of products, and these products are all compatible too with a range of Pd cross-coupling reactions, which offers further access to considerable diversification.
There is clear elegance in this work, and it will be attractive to those involved in bioactives discovery.
I only have minor comments. The isomer trans 1c is mentioned in the text, and the minor isomer of 1c is mentioned in Table 1 legend, but it is not clear what is the structure of cis and what is the structure of trans. Is cis 1c the structure shown in the Scheme? That could be clarified. The word 'Gratifyingly' is used four times in the text, this frequency could be significantly reduced. The paper is concise and impressive in its ingenuity. I am very happy to recommend publication.
Author Response: We are most grateful to the referee for this very supportive summary of the work and for recommending publication in Nature Communications. Two corrections were requested and both have been incorporated into the revised version of the manuscript. Specifically, the starting material isomers have been designated as "major-1c" (cis) and "minor-1c" (trans). We have also measured the X-ray structure of the minor (trans) isomer and added it to the Table 1 to justify the stereochemical descriptors and to also to support the mechanistic discussion (please see referee report #3). The CCDC number has also been included in the text (CCDC  2239011 minor-1c).
Finally, the excessive use of the word "Gratifyingly" has been addressed and the term now only appears once in the manuscript. Once again, we thank the expert referee for the positive and supportive comments and helpful suggestions.

• Reviewer #3 (Remarks to the Author):
This manuscript by Gilmour and coworkers describes a multi-step sequence starting from diarylcyclobutanols and furnishing fluorinated aryl-tetralins. This one-pot reaction involves acid-catalyzed SN1 of the alcohol and trapping of the carbocation intermediate with fluoride, difluorination of the alkene with phenonium rearrangement, and C-F activation leading to Friedel-Crafts cyclization. Individually, each step is known, although their combination together is innovative and non-trivial.
-Homoallylic fluorination of cyclopropylcarbinyl and/or bicyclobutonium and/or cyclobutyl cations (Marek et al, J. Am. Chem. Soc. 2020, 142, 5543-5548, which is not cited here.) -Hypervalent iodine-catalyzed fluorination of alkenes, from this paper's and other authors (references 28-36) -C-F activation of benzylic fluorides with HFIP for Friedel-Crafts (Paquin, reference 38) Author Response: We thank the referee for the very supportive and insightful comments regarding the study, and the excellent suggestions on how to strengthen it. The referee is absolutely correct that the highly relevant study from Marek and co-workers was not cited in the initial submission. This was an unintentional oversight for which we apologise unreservedly. The introduction has been modified and now contains a sentence to draw attention to the work:

"This would ultimately complement the elegant studies by Lanke and Marek on the generation of trans-1,2disubstituted homoallylic fluorides, via cyclopropinyl carbocations, from cyclopropyl carbinols.[27]"
The novel sequence reported here does allow the synthesis of complex difluorinated tetralins. Some discussion about whether this methodology is preferable to deoxofluorination of the corresponding tetralone would be warranted in order to assess how likely it is that the synthetic approach described here is better to access such compounds.
Author Response: Again, this is an excellent suggestion. To fully address the comment, a direct comparison with the direct deoxyfluorination of the corresponding tetralone (ketone) has been performed and the information has been added to the supporting information (please see below). The conventional deoxyfluorination approach using DAST delivers the product in a very low yield (18% by 19 F NMR) of the desired tetralin and the conditions lead to significant substrate degradation. By comparison, our reaction conditions compare very favourably. We hope that this fully addresses the question from the referee.
The section in the supporting information reads as follows.
"DAST (Diethylaminosulfur trifluoride) has been used in the deoxofluorination of tetralone S15 and this enables the formation of the difluorinated tetralin derivative S16 in a moderate 38% yield. 1 However, the synthesis of difluorinated aryl tetralin 3a from aryl tetralin S17 has not been described yet. Using common deoxofluorinating conditions, 2 we have demonstrated that the desired product 3a can be obtained in a yield of 18% 19 F NMR (see Figure S1). Full conversion, and substantial degradation, of the starting material S17 was observed by TLC and 1 H NMR. In comparison, this approach allows for the synthesis of this complex motif 3a in 57% isolated yield starting from the corresponding cyclobutanol 1a." Scheme S2: Comparison of different synthetic methodologies for the synthesis of difluorinated tetralin derivatives. Figure S1: 19 F crude NMR of the deoxofluorination of S17. Ethyl 2-fluoroacetate was used as the internal standard.
The functional group tolerance of the current method is moderate (mostly halogens) but yields are good considering the one-pot sequence of three chemical transformations. A mention of what functional groups are not tolerated in this reaction would be helpful to assess its limitations. Nonetheless, the authors demonstrate its use for the synthesis of a derivative of nafenopin, which showcases the potential use of this method. Of note, the Supporting Information file is nicely organized and presented. The amount and quality of the NMR characterization data is impressive, and the authors are commended for their work.
Author Response: We appreciate the comments from the referee regarding the quality of the ESI and the synthetically useful levels of efficiency. In evaluating the scope, we focussed heavily on halogens and triflates to ensure that the final products could be easily modified by cross coupling reactions. The only potential limitation of the method is with highly electron-rich arenes and this is due to the (known) competing fluorination of the ring. For an example, please see Olah and co-workers, Isr. J. Chem. 39, 207-2010Chem. 39, 207- (1999. This paper should be publishable in Nature Communications after minor revisions. Of particular importance, a proposed mechanism with detailed intermediate structures (including rearrangement steps) is needed, either as the reaction design scheme or as a final scheme. This reviewer is particularly skeptical about the proposed nature of the cyclobutyl carbocation intermediate and why it would lead to a homoallylic fluoride product. Creary (J. Org. Chem. 2020, 85, 7086-7096.) has shown that when stabilized cyclobutyl electrophiles are ionized, cyclobutyl and bicyclobutonium cations are formed but eventually provide cyclobutane/cyclobutene products, not homoallylic products.
On the other hand, Champagne (10.26434/chemrxiv-2022-h9bq3-v2) has shown that in the Marek system cyclopropylcarbinyl cations are formed and can lead to homoallylic products directly or through homoallylic cations. The latter were always higher in energy, even when the homoallylic position is tertiary and benzylic. As such, this reviewer would hypothesize that in the current system, ionization of cyclobutanols 1 eventually leads to a cyclopropylcarbinyl cation (either directly or through a cyclobutyl/bicyclobutonium intermediate), which would explain the formation of the homoallylic fluoride III without requiring the homoallylic cation II. Some discussion about these possibilities is lacking here.
Author Response: We thank the referee most sincerely for this very insightful question and for investing so much time in considering the mechanistic postulate. Whilst we fully appreciate the alternatives suggestions that are raised, many of which we considered early in the work, we believe that the ultimate support for this mechanistic proposal is the regioselectivity of the reaction which manifests itself in the product aryl tetralin. A single regioisomer is always formed and this is completely independent of the electronic nature of the two aryl substituents. The initial cation formation is interesting on account of the 1,3-diaryl substitution and, to the best of our knowledge, such species have never been investigated computationally. If a bicyclobutonium cation was indeed generated, one might reasonably expect that the pseudo-symmetric nature of the intermediate would lead to a mixture of products. This is not the case.
The seminal work by Creary (J. Org. Chem. 2020, 85, 7086-7096) does not study 1,3-diaryl substitution but it does indicate that mono-aryl-substituted systems favour addition of exogenous nucleophiles. We have recently shown that under closely similar reaction condition, bicyclobutanes form cyclobutene derivatives (via cyclobutyl cations) and that flouride can reversibly add (ACS Catal. 2022, 12, 14507-14516 -please see the top left hand side of the image shown below). However, ring contraction to form a cyclopropane only occurs in the presence of the catalysts. In this current study, we demonstrate that the initial homoallylic fluoride formation occurs by exposure to HF.
Regarding the relative stabilities of the cations proposed, the cyclobutyl cation is tertiary but the aryl ring is twisted to minimise destabilising-non-covalent interactions (1,3-allylic strain). We therefore propose that rearrangement to form the secondary benzylic cation, in which the stabilising effect of the neighbouring π-system is not impeded, is reasonable and accounts for the selective formation of the intermediate.
To further support our hypothesis, we have attained an X-ray structure of the carbinol starting material (in this case minor-1c (trans), please see below) that shows that the aryl ring is rotated out of place. Whilst this is not directly comparable with the cation, in both cases 1,3-allylic strain will position the plane of the phenyl ring orthogonal to the empty p-orbital thereby minimising any stabilising effect. Rearrangement induced by steric decompression generates the secondary benzylic cation in which the stabilising influence of the aryl group is not impeded by the cyclic scaffold. We believe that these resonance structures provide support for the experimentally observed regioselectivity of the transformation and the insensitivity of the process to changes in the electronic nature of the aryl ring. The latter point speaks against (pseudo)-symmetric bicyclobutonium-like species.
The most compelling evidence that speaks against the formation of a transient cyclopropylcarbinyl cation stems from the work of Li and co-workers (Org. Lett. 2021, 23, 3088-3093; please see below). The authors demonstrate that exposure of aryl-substituted methylenecyclopropanes to Selectfluor® and HF (i.e. uncatalysed like the initial steps of our cascade), trigger a Wagner-Meerwein rearrangement to form a difluorocyclobutane. The cyclopropylcarbinyl cation that is formed does not lead to the homoallylic fluoride observed in our study.
The elegant work by Champagne on the venerable Marek-type cations (10.26434/chemrxiv-2022-h9bq3-v2) is certainly very interesting but cation generation is never investigated starting from ionisation of the cyclobutanol, but rather from the cyclopropanol. It is also important to note that this generates an (internal) 1,2-disubstituted alkene and not the 1,1-disubstituted alkene that is required for the catalysed difluorination / rearrangement step. Under these reaction conditions, 1,2-disubstituted alkenes are recalcitrant to I(I/III)-mediated difluorination. In the earlier work by Marek (J. Am. Chem. Soc. 2020, 142, 12, 5543-5548), the authors also report that the alkene motif of the product homoallylic fluoride is 1,2-disubstituted and not 1,1-as observed here.
We hope that these comments address the referee´s sufficiently and appreciate the very thoughtful mechanistic questions. The referee is quite right that a discussion of the factors that led to our mechanistic hypothesis would enhance the text and so we have added the following statements to the paper, which cite the important studies that the referee has highlighted. Starting on p4, line 17: "It is pertinent to mention that crystals of the trans isomer of the starting cyclobutanol (minor-1c) could be isolated and subjected to X-ray diffraction analysis (see Table 1  "It is interesting to note that the transformation is characterised by formation of a single regioisomer, which further supports the mechanistic framework in Fig. 1 and is difficult to reconcile with the formation of a bicyclobutonium intermediate." Minor comments: -Compounds are all racemic, could it be indicated as so in the schemes?
Author Response: This is an excellent suggestion. The manuscript has been modified accordingly and the "±" sign has been added to denote that the products are racemic.
-That Olah's reagent is Py•HF is not indicated anywhere in the manuscript. Also, how the amine•HF mixtures are made using Et3N•3HF and Py•HF should be discussed somewhere in the text.
Author Response: This information is provided in the supporting information with a full description. An additional reference to the ESI was added to the text.

"(see ESI for further information on the preparation of amine:HF mixtures)"
-The impact of solvent quantities should probably be discussed as a function of solute concentration rather than solvent volume (0.5 -2mL), to make it more general.
this preliminary data matches with the known literature that indicates that homoallylic cations are high in energy, relative to cyclopropylcarbinyl or cyclobutyl/bicyclobutonium structures. The authors should not use that data in their paper, but their proposal should discuss the possibilities, and especially the known instability of homoallylic cations.
In addition, I believe the authors have misinterpreted the Li study (discussed on page 2, line 22) and that section of the paper should rephrased. Li's reaction involves a cyclopropylcarbinyl cation that is presumed to prefer the cyclobutyl/bicyclobutonium form due to the fluorine's stabilization of α-cations. This cyclobutyl cation is what presumably leads to a cyclobutyl product. This is similar to Creary's work, where a cyclobutyl cation leads to a cyclobutyl product. In the current study a homoallylic fluoride is formed but as shown above it looks like the cyclobutyl cation is more stable, so this interesting fact needs to be contrasted to previous work and compared to the Marek reaction.
I would also disagree with the authors' claim on page 8, line 7 that the formation of a single regiosisomer is due to a specific cation (also in the rebuttal letter). Even in complex cyclopropylcarbinyl/bicyclobutonium cations, one nucleophilic attack is usually much more favored energetically, so even a bridged structure could lead to the homoallylic fluoride specifically (see Marek's paper). As was shown above, this experimental observation does not need a homoallylic cation as the major intermediate, but the intermediate that leads to their product might be a cyclopropylcarbinyl/homoallyl hybrid structure.
Finally, the authors name the cyclopropylcarbinyl cations as "cyclopropinyl" in a few instances, which should be corrected. Once these issues are addressed, the manuscript should be publishable in Nature Communications since the quality and importance of the results remain high.